In a small trial of advanced chronic lymphocytic leukemia (CLL) patients, genetically modified versions of their own T cells behaved like "serial killers" and hunted down and obliterated tumors, resulting in sustained remissions of up to a year. The breakthrough gene therapy treatment has been 20 years in the making, and provides a roadmap for other cancers, say researchers from the University of Pennsylvania's Abramson Cancer Center and Perelman School of Medicine, who report the results in a study published today, 11 August, in two journals: the New England Journal of Medicine and Science Translational Medicine.
The pilot trial of three patients is the first to show how gene transfer therapy can create "serial killer" T cells aimed at cancerous tumors, and the team, led by senior author Dr Carl June, director of Translational Research and a professor of Pathology and Laboratory Medicine in the Abramson Cancer Center, believe the protocol they have developed can be used to develop treatments for other cancers, including ovarian and lung cancers, and myeloma and melanoma.
The three patients in the trial had advanced CLL and their only hope of a cure was a bone marrow transplant, a procedure that requires long stays in hospital and carries a 1 in 5 chance of death. Even then, the chance of a cure is at best 50%, said the researchers.
For the study, the researchers removed patients' own T cells (a type of white blood cell), modified them in Penn's vaccine production labs, then infused them back into the patients' bodies after chemotherapy.
June told the press that the treatment worked much better than they thought it would:
"Within three weeks, the tumors had been blown away, in a way that was much more violent than we ever expected."
Co-senior investigator Dr David Porter, professor of Medicine and director of Blood and Marrow Transplantation at Penn, said:
"Most of what I do is treat patients with no other options, with a very, very risky therapy with the intent to cure."
"This approach has the potential to do the same thing, but in a safer manner," he explained.
June said after the patients received their modified T cells, they replicated more than 1,000-fold in each patient. "Drugs don't do that," he said.
The T cells not only replicated themselves profusely, but each T cell killed thousands of tumor cells: they were literally "serial killers". Overall, they destroyed at least two pounds of tumor in each patient, said June.
The reason this trial appears to have achieved miraculous results when other trials using modified T cells have been disappointing, is because of several "secret ingredients" as June describes them. These include the fact the modified T cells targeted specific cells only, leaving healthy cells intact, thus fewer side effects, and also, when it meets a target cell, the modified T cell sends out signals that trigger other T cells to replicate, the result being a vast, self-multiplying growth in numbers of T cells that overwhelm the tumor and obliterate it.The researchers write about the immunotherapy and how they reprogrammed the T cells in theScience Translational Medicine paper, while the New England Journal of Medicine deals with the effects of T cell replication in the case of one patient.
The researchers genetically modified the T cells they removed from the patients using a lentivirus vector. This gives the T cell the ability to express an antibody called chimeric antigen receptor (CAR). The CAR, which sits on the surface of the cell, with a part submerged also inside the cell, binds to a specific antigen, a protein called CD19, which is expressed only on certain other cells, including CLL tumor cells and normal B cells (another type of white blood cell). The act of binding CAR to CD19 initiates cell death in the target cell.
Once they start to express CAR, the T cells focus all their killing on cells that express CD19, ignoring all other cells. This greatly helps to minimize the side effects normally seen in standard therapies.
But the team went further than just give the T cells the ability to express CAR: they engineered a signalling molecule inside the CAR, the part that sits inside the cell. This signalling molecule is activated when the CAR binds to CD19, and produces cytokines that tell other T cells to multiply, creating an avalanche of serial killer T cells.
The NEJM paper describes how one patient, a 64-year-old man, responded to this treatment. When he joined the study, his bone marrow was riddled with tumor cells. Then he received his treatment, and for the first two weeks, nothing seemed to be happening.
But, on day 14, he started having chills, nausea, fever, and other symptoms, and tests showed a huge increase in T cells in his blood. He had tumor lysis syndrome, which is when a lot of cancer cells die in a short space of time.
But only two weeks later, by day 28 after treatment, he had recovered from tumor lysis syndrome, and tests on his blood and marrow showed no signs of leukemia.
Porter said:
"This massive killing of tumor is a direct proof of principle of the concept."
The cell culture method that the researchers used also resurrected T cells that the leukemia had suppressed, causing the generation of "memory" T cells, which they hope will give patients ongoing protection against the cancer recurring.
Although this study was not designed to test the long term effects of the treatment, there is evidence, nonetheless, that months after infusion, the new cells had replicated and were able to continue killing cancer cells throughout the patients' bodies.
The team now plans to test their CAR-CD19 method on patients with other types of CD19-positive cancers, such as non- Hodgkin's lymphoma and acute lymphocytic leukemia, and they plan to study how they might apply it to pediatric leukemia patients, where standard therapy has not been able to help them.
The team has also created a CAR vector that binds to another protein, mesothelin, which is expressed by mesothelioma cancer cells, and also by ovarian and pancreatic cancer cells.
Funds from the Leukemia & Lymphoma Society, and the Alliance for Cancer Gene Therapy, founded by Penn graduates Barbara and Edward Netter, helped pay for the study.
Written by Catharine Paddock PhD
No comments:
Post a Comment